Periodic Reporting for period 4 - PACE (A multicenter phase IIb study using HLA-unmatched allogeneic placenta-derived stromal cells (PLX-PAD) for the treatment of severe critical limb ischemia accompanied by mechanistic studies)
Période du rapport: 2021-07-01 au 2021-12-31
What is the problem/issue being addressed?
Critical limb ischemia (CLI) is at the severe end of peripheral artery disease (PAD) spectrum when limb perfusion is reduced to tissue loss. Nutrient blood flow to the tissues and microcirculation exchange are seriously affected. As such CLI is associated with irreversible disability due to limb amputation, increased mortality rates and overall poor quality of life. Therapies targeting only the re-establishment of vascular patency (revascularization) and/or nascent collateral vessel formation by supporting vascularization have proven ineffective in a significant proportion of patients indicating the ischemic muscle tissue is not dispensable and therefore a “restoration of flow approach” is not independently sufficient to rescue the limb. Indeed, it is likely that myopathy and vasculopathy are interrelated components of a coordinated tissue response to CLI. Thus, current clinical interventions are largely ineffective and therapeutic angiogenesis-based trials have shown limited if any efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. The PACE placebo-controlled randomized clinical phase III trial is testing PLX-PAD placenta stromal cell therapy as novel therapeutic option for CLI, accompanied by biomarker and mechanistic studies to decipher the underlying clinical response profiles and mechanisms of action.
Why is it important for society?
PACE aimed for advancing clinical application of the “off-the-shelf” allogeneic placenta-derived stromal cell product (PLX-PAD) for critical limb ischemia (CLI) – a clinical indication with high unmet medical need – by performing a pivotal clinical trial integrated with mechanism-based research.
Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death (most studies report on 1-year amputation-free survival <60%; 10-year mortality 70%). CLI has a strong social impact and its incidence is rising worldwide, including in Europe. The prevalence of CLI in the population aged 60–90 years is estimated as 0.5–1.2% with male to female ratio around 3:1. Major risk factors for PAD include smoking, hyperlipidemia, hypertension, and, particularly for the development of CLI and diabetes. Diabetic patients are five-fold more likely to develop CLI than non-diabetic patients. The application of gene- and cell-based ATMP therapies to promote angiogenesis has been proposed as a novel concept to treat lower-limb CLI, particularly for patients with no options for revascularization. Proof of concept was demonstrated in animal models leading to clinical trials. The safety of these biologic therapies has been demonstrated, with no evidence of "off-target" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Despite some failures particularly with single gene therapy, the results obtained from the recently published literature indicate a putative beneficial role of cell therapy, e.g. in ameliorating ischemic symptoms in CLI patients and improving their quality of life. However, there are several open questions regarding the optimal cell types, dosing, route of administration, combination, patient phenotype, and most critically, the proof of efficacy in large, well-controlled, and sufficiently powered clinical trials. In particular biomarker and mode-of-action (MoA) studies are of importance to better understand clinical trial outcomes. Thus, there is a need for i) well characterized off-the-shelf cell products manufactured in well-controlled, scalable, and robust GMP-procedures; and ii) more detailed analyses of patients prior to cell treatment to better define stratification parameters; and iii) an improved understanding on pharmacodynamics; and iv) to better understand the underlying MoA and to identify responders and non-responders to treatment or adverse effects as early as possible via state of the art biomarkers.Beyond the the primary goal of the study, to prove the usefulness of PLX cell therapy for combating severe CLI, we can learn many things from the project, such as i) heterogeneity of late stage CLI, ii) impact of intense gold-standard medical care (placebo arm) on course of severe disease, iii) comparability of cell products from different lots or even different sources (placenta donor), iv) in-depth profiling of PLX cell product that might be useful for other indications, v) standardized biomarker program applicable for different clinical studies.
Critical limb ischemia (CLI) is at the severe end of peripheral artery disease (PAD) spectrum when limb perfusion is reduced to tissue loss. Nutrient blood flow to the tissues and microcirculation exchange are seriously affected. As such CLI is associated with irreversible disability due to limb amputation, increased mortality rates and overall poor quality of life. Therapies targeting only the re-establishment of vascular patency (revascularization) and/or nascent collateral vessel formation by supporting vascularization have proven ineffective in a significant proportion of patients indicating the ischemic muscle tissue is not dispensable and therefore a “restoration of flow approach” is not independently sufficient to rescue the limb. Indeed, it is likely that myopathy and vasculopathy are interrelated components of a coordinated tissue response to CLI. Thus, current clinical interventions are largely ineffective and therapeutic angiogenesis-based trials have shown limited if any efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. The PACE placebo-controlled randomized clinical phase III trial is testing PLX-PAD placenta stromal cell therapy as novel therapeutic option for CLI, accompanied by biomarker and mechanistic studies to decipher the underlying clinical response profiles and mechanisms of action.
Why is it important for society?
PACE aimed for advancing clinical application of the “off-the-shelf” allogeneic placenta-derived stromal cell product (PLX-PAD) for critical limb ischemia (CLI) – a clinical indication with high unmet medical need – by performing a pivotal clinical trial integrated with mechanism-based research.
Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death (most studies report on 1-year amputation-free survival <60%; 10-year mortality 70%). CLI has a strong social impact and its incidence is rising worldwide, including in Europe. The prevalence of CLI in the population aged 60–90 years is estimated as 0.5–1.2% with male to female ratio around 3:1. Major risk factors for PAD include smoking, hyperlipidemia, hypertension, and, particularly for the development of CLI and diabetes. Diabetic patients are five-fold more likely to develop CLI than non-diabetic patients. The application of gene- and cell-based ATMP therapies to promote angiogenesis has been proposed as a novel concept to treat lower-limb CLI, particularly for patients with no options for revascularization. Proof of concept was demonstrated in animal models leading to clinical trials. The safety of these biologic therapies has been demonstrated, with no evidence of "off-target" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Despite some failures particularly with single gene therapy, the results obtained from the recently published literature indicate a putative beneficial role of cell therapy, e.g. in ameliorating ischemic symptoms in CLI patients and improving their quality of life. However, there are several open questions regarding the optimal cell types, dosing, route of administration, combination, patient phenotype, and most critically, the proof of efficacy in large, well-controlled, and sufficiently powered clinical trials. In particular biomarker and mode-of-action (MoA) studies are of importance to better understand clinical trial outcomes. Thus, there is a need for i) well characterized off-the-shelf cell products manufactured in well-controlled, scalable, and robust GMP-procedures; and ii) more detailed analyses of patients prior to cell treatment to better define stratification parameters; and iii) an improved understanding on pharmacodynamics; and iv) to better understand the underlying MoA and to identify responders and non-responders to treatment or adverse effects as early as possible via state of the art biomarkers.Beyond the the primary goal of the study, to prove the usefulness of PLX cell therapy for combating severe CLI, we can learn many things from the project, such as i) heterogeneity of late stage CLI, ii) impact of intense gold-standard medical care (placebo arm) on course of severe disease, iii) comparability of cell products from different lots or even different sources (placenta donor), iv) in-depth profiling of PLX cell product that might be useful for other indications, v) standardized biomarker program applicable for different clinical studies.
The PACE clinical trial has been terminated after 213 of 246 patients were recruited, because of recommendation by the DSMB based on their interim analysis revealing that the achievement of the primary endpoint was unlikely. On 07 March 2021 Data Base Lock (DBL) was performed. Clinical data analysis has been completed by the end of 2021, to improve our understanding if secondary endpoints and/or patient subgroup analyses reveal a treatment effect for PLX-PAD. This analysis is critical for the decision how to proceed with this indication and what we can we learn for future trials in CLI, as no new drug was approved during the last decade. In-depth analysis of the cell product characterization data has confirmed the robustness of PLX-PAD manufacturing for clinical use. Follow-up clinical and biomarker examinations of the study patients, such as blood serum/plasma cytokine biomarker analysis, circulating blood cell transcriptome analysis with next-generation sequencing (NGS / RNAseq), and PLX-directed alloimmune responsiveness studies (cellular and humoral response) of patients have been completed, to increase our understanding on the MoA of PLX-PAD in vivo. This is further supported by in vitro modeling of the putative MoA of PLX-PAD in preclinical model systems, such as the (multi)-organ-on-chip model. All preclinical and clinical data were combined in a database/repository to be available after project completion. Altogether PACE can be considered a model for advancing the clinical development of ATMPs by an integrative approach based on a very well-defined cell product, a state-of-the-art clinical trial, and accompanying biomarker and mechanistic in-patients studies. Importantly, for public benefit and maximum transparency we are now preparing the publication of the obtained study results with adjunct clinical response biomarker analysis and cell product characterization.
The PACE consortium is investigating the efficacy of a cell-based regenerative treatment for patients with CLI and minor tissue loss, who are unsuitable for revascularization. The treatment is an off-the-shelf allogeneic placenta-derived stromal cell product. PACE is a valuable example of Public-Private investment that could improve the quality of life of patients affecting by CLI/PAD. Although the trial failed to achieve the primary endpoint in the overall population, the PACE study has delivered a lot of information useful for developing a new therapy option for patients suffering from late-stage critical limb ischemia (CLI), a disease with high medical need and limited treatment options. Moreover, it demonstrates that an off-the-shelf manufacturing of an allogenic cell product is feasible, robust, and safe with high lot-to-lot and donor-to-donor consistency.